rs151148684

Variant names:

• chrX-153725737-A-G
• rs151148684
• NM_000033.4:c.471A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000033.4(ABCD1):​c.471A>G​(p.Gln157Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000893 in 1,211,108 control chromosomes in the GnomAD database, including 6 homozygotes. There are 311 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., 167 hem., cov: 26)
  • Exomes 𝑓: 0.00050 (4 hom. 144 hem.)
• Consequence: ABCD1 NM_000033.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.27
• Publications: 2 publications found

Genes affected

ABCD1 (HGNC:61): (ATP binding cassette subfamily D member 1) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. This peroxisomal membrane protein is likely involved in the peroxisomal transport or catabolism of very long chain fatty acids. Defects in this gene have been identified as the underlying cause of adrenoleukodystrophy, an X-chromosome recessively inherited demyelinating disorder of the nervous system. [provided by RefSeq, Jul 2008]

BCAP31 (HGNC:16695): (B cell receptor associated protein 31) This gene encodes a member of the B-cell receptor associated protein 31 superfamily. The encoded protein is a multi-pass transmembrane protein of the endoplasmic reticulum that is involved in the anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi and in caspase 8-mediated apoptosis. Microdeletions in this gene are associated with contiguous ABCD1/DXS1375E deletion syndrome (CADDS), a neonatal disorder. Alternative splicing of this gene results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 16. [provided by RefSeq, Jan 2012]

BCAP31 Gene-Disease associations (from GenCC):

• severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome

  Inheritance: AR, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-153725737-A-G is Benign according to our data. Variant chrX-153725737-A-G is described in ClinVar as Benign. ClinVar VariationId is 458645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00467 (530/113570) while in subpopulation AFR AF = 0.0165 (518/31367). AF 95% confidence interval is 0.0153. There are 2 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 530 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.471A>G	p.Gln157Gln	synonymous	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.471A>G	p.Gln157Gln	synonymous	Exon 1 of 11	NP_001427676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.471A>G	p.Gln157Gln	synonymous	Exon 1 of 10	ENSP00000218104.3	P33897
	BCAP31	ENST00000862067.1		c.-56T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000532126.1
	BCAP31	ENST00000968754.1		c.-56T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000638813.1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 528 AN: 113516 Hom.: 2 Cov.: 26

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000736

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00196

GnomAD2 exomes AF: 0.00130 AC: 236 AN: 182060 AF XY: 0.000906

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000503 AC: 552 AN: 1097538 Hom.: 4 Cov.: 32 AF XY: 0.000396 AC XY: 144 AN XY: 363274

African (AFR) AF: 0.0180 AC: 474 AN: 26400

American (AMR) AF: 0.000398 AC: 14 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39944

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4136

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 842051

Other (OTH) AF: 0.00106 AC: 49 AN: 46085

GnomAD4 genome AF: 0.00467 AC: 530 AN: 113570 Hom.: 2 Cov.: 26 AF XY: 0.00467 AC XY: 167 AN XY: 35724

African (AFR) AF: 0.0165 AC: 518 AN: 31367

American (AMR) AF: 0.000735 AC: 8 AN: 10882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2663

East Asian (EAS) AF: 0.00 AC: 0 AN: 3616

South Asian (SAS) AF: 0.00 AC: 0 AN: 2840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53382

Other (OTH) AF: 0.00194 AC: 3 AN: 1548

Alfa AF: 0.00239 Hom.: 12

Bravo AF: 0.00502

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Adrenoleukodystrophy (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.0
DANN	Benign	0.53
PhyloP100		3.3
PromoterAI		-0.0026	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs151148684; hg19: chrX-152991192;